Emerging viral pathogens present a critical threat to U.S. health and economy. Nipah (NiV) and Hendra (HeV) viruses are members of the newly defined Henipavirus genus of the Paramyxoviridae. Nipah virus (NiV) is an emergent paramyxovirus that causes fatal encephalitis in up to 74% of infected patients, and there is increasing evidence of human-to-human transmission. NiV and HeV are designated as BSL4 and priority pathogens in the NIAID Biodefense Research Agenda. NiV, in particular, could be a devastating agent of agrobioterrorism if used against the pig farming industry. Endothelial syncytia are a pathognomonic feature of NiV infections, and are mediated by the fusion (F) and attachment (G) envelope glycoproteins. We recently identified ephrinB2 as the NiV and HeV receptor, and the expression of ephrinb2 on endothelial cells and neurons largely explains the known cellular tropism of both NiV amd HeV. The identification of the NiV receptor has shed light on the pathobiology of NiV infection, and can spur the rational development of effective therapeutics. In particular, we have used our knowledge of NiV-receptor interactions and the Molecular Screening Shared Resource at UCLA to screen small molecule chemical libraries, and have obtained candidate small molecule antagonists that block NiV envelope interactions with its cognate receptor. In response to RFA-AI-05-019 (Co-operative Research Partnership for Biodefense), we have proposed a highly collaborative, inter-disciplinary, and trans-center research effort that will synergize the synthetic organic chemistry expertise of Dr. Michael Jung (co-PI), the virus-receptor interaction expertise of the Dr. Benhur Lee (PI), and the biodefense and BSL4 virological expertise of Dr. Ramon Flick (co-Pi at UTMB, Galveston), to develop a therapeutic against NiV. We propose the following Specific Aims that are geared towards the identification of a lead compound that can be developed into a therapeutic against NiV, and likely, HeV. They are: (1) To develop small molecule antagonists that block NiV and HeV entry, and (2) To assess the anti-viral efficacy of these small molecule entry inhibitors in live virus challenge experiments under BSL4 conditions. Aim 1 exploits the infrastructure and inter-disciplinary expertise already present at UCLA to identify and optimize entry inhibitors of NiV, and Aim 2 makes use of the already sizable federal investment in the BSL4 facilities at UTMB, Galveston. Dr. Ramon Flick is the co-director of the BSL4 facility at UTMB, Galveston, and has already collaborated with the PI on NiV entry experiments. Public Health Relevance: Nipah and Hendra viruses are designated priority pathogens, are deadly, and can be devastating agents of bioterrorism and agroterrorism (devastation of the live-stock industry). The proposed studies, if successful, will lead to the development of effective anti-Nipah (and Hendra) therapeutics that can be used in response to an outbreak of these priority pathogens.